Antithetical impacts of deleterious LRP1B mutations in non-squamous and squamous NSCLCs on predicting benefits from immune checkpoint inhibitor alone or with chemotherapy over chemotherapy alone: retrospective analyses of the POPLAR/OAK and CHOICE-01 trial

作     者：Jinliang Wang Wenyong Zhou Yu Xu Jianchun Duan Qiaoxia Zhou Guoqiang Wang Leo Li Chunwei Xu Wenxian Wang Shangli Cai Zhijie Wang Jie Wang 

作者机构：Department of OncologyThe Fifth Medical Center of Chinese PLA General Hospital Department of Thoracic SurgeryShanghai Chest HospitalSchool of MedicineShanghai Jiao Tong University Burning Rock Biotech CAMS Key Laboratory of Translational Research on Lung CancerState Key Laboratory of Molecular OncologyDepartment of Medical OncologyNational Cancer Center/National Clinical Research Center for ancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of Sciences Department of Clinical TrialThe Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) 

出 版 物：《Science China Life Sciences》 (中国科学:生命科学(英文版))

年 卷 期：2025年第68卷第1期

页      面：249-262页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (82170108, 81700092, 81871889, 82072586, 81630071) the Clinical Research Projects in Health industry of Shanghai Municipal Health Commission (202340017) the Foundation of the Center for Medical and Engineering Interdisciplinary Innovation, University of Shanghai for Science and Technology (2023GD-XK08Z) the National Youth Talent (to Z. Wang) Basic Research Foundation of Shanghai Chest Hospital (2020YNJCM05) the National Key Research and Development Project of China (2022YFC2505004, 2022YFC2505000) CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012) CAMS Key lab of translational research on lung cancer (2018PT31035) Beijing Natural Science Foundation (7212084) 

主　　题：non-squamous NSCLC squamous NSCLC LRP1B deleterious mutations predictive biomarker immune checkpoint inhibitor 

摘      要：In non-small cell lung cancers,the non-squamous and squamous subtypes（nsqNSCLC and sqNSCLC） exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor（ICI）-based *** our inhouse training cohort（n=85）,the presence of the LRP1B deleterious mutation（LRP1B-del） was associated with longer and shorter progression-free survival（PFS） on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteraction0.001).Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs（P=0.040） and sqNSCLCs（P=0.014）,*** the POPLAR/OAK cohort,nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel(hazard ratio（HR）=0.70,P=0.046),whereas this benefit was negligible in those without LRP1B-del（HR=1.05,P=0.64）.Conversely,sqNSCLCs without LRP1B-del benefited more from atezolizumab（HR=0.60,P=0.002） than those with LRP1B-del（HR=1.30,P=0.31）.Consistent results were observed in the in-house CHOICE-01 cohort,in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone(Pinteraction=0.008).This multi-cohort study delineates the antithetical impacts of LRP1B-del in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy *** findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs,emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.